ORCID Profile
0000-0002-8630-0121
Current Organisation
Flinders University
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Manufacturing Engineering | Manufacturing Processes and Technologies (excl. Textiles) | Microtechnology
Publisher: American Chemical Society (ACS)
Date: 18-02-2022
Publisher: Elsevier BV
Date: 02-2008
DOI: 10.1016/J.BMCL.2008.01.023
Abstract: Chemokines are small molecular weight water-soluble proteins playing a key role in immunomodulation and host-defense mechanisms. CCR2 receptor is targeted for diseases like arthritis, multiple sclerosis, vascular disease, obesity, and type 2 diabetes. Reported, herein are the QSAR studies performed on a erse set of enantiopure analogues reported as CCR2 antagonists by hologram analysis. The best model highlights the importance of chirality feature in comparison with the other models developed without the chirality. The validated model showed high internal and external predictive power. The robustness of the model was achieved with good statistical r(2) of 0.945 and cross-validated r(cv)(2) of 0.837. The challenging test predictivity of the model was confirmed with r(pred)(2) of 0.807. The fragment fingerprints help in understanding essential pharmacophoric features for CCR2 antagonism and provide basis for SAR of the molecules. The 2D contribution maps with fragment information will be useful for the design of novel CCR2 antagonists having improved efficacy.
Publisher: MDPI AG
Date: 24-02-2023
DOI: 10.3390/ANTIBIOTICS12030463
Abstract: Oxazolidinones are a broad-spectrum class of synthetic antibiotics that bind to the 50S ribosomal subunit of Gram-positive and Gram-negative bacteria. Many crystal structures of the ribosomes with oxazolidinone ligands have been reported in the literature, facilitating structure-based design using methods such as molecular docking. It would be of great interest to know in advance how well docking methods can reproduce the correct ligand binding modes and rank these correctly. We examined the performance of five molecular docking programs (AutoDock 4, AutoDock Vina, DOCK 6, rDock, and RLDock) for their ability to model ribosomal–ligand interactions with oxazolidinones. Eleven ribosomal crystal structures with oxazolidinones as the ligands were docked. The accuracy was evaluated by calculating the docked complexes’ root-mean-square deviation (RMSD) and the program’s internal scoring function. The rankings for each program based on the median RMSD between the native and predicted were DOCK 6 AD4 Vina RDOCK RLDOCK. Results demonstrate that the top-performing program, DOCK 6, could accurately replicate the ligand binding in only four of the eleven ribosomes due to the poor electron density of said ribosomal structures. In this study, we have further benchmarked the performance of the DOCK 6 docking algorithm and scoring in improving virtual screening (VS) enrichment using the dataset of 285 oxazolidinone derivatives against oxazolidinone binding sites in the S. aureus ribosome. However, there was no clear trend between the structure and activity of the oxazolidinones in VS. Overall, the docking performance indicates that the RNA pocket’s high flexibility does not allow for accurate docking prediction, highlighting the need to validate VS. protocols for ligand-RNA before future use. Later, we developed a re-scoring method incorporating absolute docking scores and molecular descriptors, and the results indicate that the descriptors greatly improve the correlation of docking scores and pMIC values. Morgan fingerprint analysis was also used, suggesting that DOCK 6 underpredicted molecules with tail modifications with acetamide, n-methylacetamide, or n-ethylacetamide and over-predicted molecule derivatives with methylamino bits. Alternatively, a ligand-based approach similar to a field template was taken, indicating that each derivative’s tail groups have strong positive and negative electrostatic potential contributing to microbial activity. These results indicate that one should perform VS. c aigns of ribosomal antibiotics with care and that more comprehensive strategies, including molecular dynamics simulations and relative free energy calculations, might be necessary in conjunction with VS. and docking.
Publisher: American Chemical Society (ACS)
Date: 30-03-2011
DOI: 10.1021/CT1007229
Abstract: A fundamental challenge in computational drug design is the availability of reliable and validated experimental binding and structural data against which theoretical calculations can be compared. In this work a combination of molecular dynamics (MD) simulations and free energy calculations has been used to analyze the structural and thermodynamic basis of ligand recognition by phenylethanolamine N-methyltransferase (PNMT) in an attempt to resolve uncertainties in the available binding and structural data. PNMT catalyzes the conversion of norepinephrine into epinephrine (adrenaline), and inhibitors of PNMT are of potential therapeutic importance in Alzheimer's and Parkinson's disease. Excellent agreement between the calculated and recently revised relative binding free energies to human PNMT was obtained with the average deviation between the calculated and the experimentally determined values being only 0.8 kJ/mol. In this case, the variation in the experimental data over time is much greater than the uncertainties in the theoretical estimates. The calculations have also enabled the refinement of structure-activity relationships in this system, to understand the basis of enantiomeric selectivity of substitution at position three of tetrahydroisoquinoline and to identify the role of specific structural waters. Finally, the calculations suggest that the preferred binding mode of trans-(1S,2S)-2-amino-1-tetralol is similar to that of its epimer cis-(1R,2S)-2-amino-1-tetralol and that the ligand does not adopt the novel binding mode proposed in the pdb entry 2AN5 . The work demonstrates how MD simulations and free energy calculations can be used to resolve uncertainties in experimental binding affinities, binding modes, and other aspects related to X-ray refinement and computational drug design.
Publisher: Elsevier BV
Date: 02-2008
DOI: 10.1016/J.JMGM.2007.06.006
Abstract: Mutagenicity and carcinogenicity are toxicological endpoints which pose a great concern being the major determinants of cancers and tumours. Nitroarenes possess genotoxic properties as they can form various electrophilic intermediates and adducts with biological systems. Different QSTR techniques were employed to develop models for the prediction of mutagenicity of nitroarenes using a erse set of 197 nitro aromatic and hetero aromatic molecules. The 2D and 3D QSTR methods used for model development gave statistically significant results. The alignment for 3D methods was obtained by maximum common substructures (MCS) approach, by taking the most mutagenic molecule of the dataset as the template. All the QSTR models were developed with the same set of training and test set molecules. The 3D contours and 2D contribution maps along with molecular fingerprints provide useful information about the mutagenic potentials of the molecules. The GFA based model shows thermodynamic and topological descriptors play an important role in characterizing mutagenicity of nitroarenes. Atomic-level thermodynamic descriptor namely AlogP throws light on hydrophobic features and helps to understand the bilinear model. Topological aspects of these classes of compounds were depicted by the fragment fingerprints and Balaban indices obtained from HQSAR and GFA models, respectively. The predictive abilities of 2D and 3D QSTR models may be useful as a vibrant predictive tool to screen out mutagenic nitroarenes and design safer non-mutagenic nitro compounds.
Publisher: American Association for Cancer Research (AACR)
Date: 09-2023
Publisher: Springer Science and Business Media LLC
Date: 10-08-2022
DOI: 10.1038/S41380-021-01250-7
Abstract: Current medications for schizophrenia typically modulate dopaminergic neurotransmission. While affecting positive symptoms, antipsychotic drugs have little clinical effect on negative symptoms and cognitive impairment. Moreover, newer 'atypical' antipsychotic drugs also have significant metabolic adverse-effects. The recent positive clinical trial of the novel drug candidate SEP-363856, which targets non-dopamine receptors (trace amine-associated receptor and the 5HT
Publisher: American Society for Pharmacology & Experimental Therapeutics (ASPET)
Date: 22-03-2019
Abstract: Protein kinase inhibitors (KIs), which are mainly biotransformed by CYP3A4-catalyzed oxidation, represent a rapidly expanding class of drugs used primarily for the treatment of cancer. Ligand- and structure-based methods were applied here to investigate whether computational approaches may be used to predict the site(s) of metabolism (SOM) of KIs and to identify amino acids within the CYP3A4 active site involved in KI binding. A data set of the experimentally determined SOMs of 31 KIs known to undergo biotransformation by CYP3A4 was collated. The structure-based (molecular docking) approach employed three CYP3A4 X-ray crystal structures to account for structural plasticity of this enzyme. Docking pose and SOM predictivity were influenced by the X-ray crystal template used for docking and the scoring function used for ranking binding poses. The best prediction of SOM (77%) was achieved using the substrate (bromoergocryptine)-bound X-ray crystal template together with the potential of mean force score. Binding interactions of KIs with CYP3A4 active site residues were generally similar to those observed for other substrates of this enzyme. The ligand-based molecular superposition approach, using bromoergocryptine from the X-ray cocrystal structure as a template, poorly predicted (42%) the SOM of KIs, although predictivity improved to 71% when the docked conformation of sorafenib was used as the template. Among the web-based approaches examined, all web servers provided excellent predictivity, with one web server predicting the SOM of 87% of the data set molecules. Computational approaches may be used to predict the SOM of KIs, and presumably other classes of CYP3A4 substrates, but predictivity varies between methods.
Publisher: MDPI AG
Date: 13-11-2020
Abstract: ADME genes are a group of genes that are involved in drug absorption, distribution, metabolism, and excretion (ADME). The expression profiles of ADME genes within tumours is proposed to impact on cancer patient survival however, this has not been systematically examined. In this study, our comprehensive analyses of pan-cancer datasets from the Cancer Genome Atlas (TCGA) revealed differential intratumoral expression profiles for ADME genes in 21 different cancer types. Most genes also showed high interin idual variability within cancer-specific patient cohorts. Using Kaplan-Meier plots and logrank tests, we showed that intratumoral expression levels of twenty of the thirty-two core ADME genes were associated with overall survival (OS) in these cancers. Of these genes, five showed significant association with unfavourable OS in three cancers, including SKCM (ABCC2, GSTP1), KIRC (CYP2D6, CYP2E1), PAAD (UGT2B7) sixteen showed significant associations with favourable OS in twelve cancers, including BLCA (UGT2B15), BRCA (CYP2D6), COAD (NAT1), HNSC (ABCB1), KIRC (ABCG2, CYP3A4, SLC22A2, SLC22A6), KIRP (SLC22A2), LIHC (CYP2C19, CYP2C8, CYP2C9, CYP3A5, SLC22A1), LUAD (SLC15A2), LUSC (UGT1A1), PAAD (ABCB1), SARC (ABCB1), and SKCM (ABCB1, DYPD). Overall, these data provide compelling evidence supporting ADME genes as prognostic biomarkers and potential therapeutic targets. We propose that intratumoral expression of ADME genes may impact cancer patient survival by multiple mechanisms that can include metabolizing/transporting anticancer drugs, activating anticancer drugs, and metabolizing/transporting a variety of endogenous molecules involved in metabolically fuelling cancer cells and/or controlling pro-growth signalling pathways.
Publisher: Springer Science and Business Media LLC
Date: 17-03-2023
Publisher: American Association for Cancer Research (AACR)
Date: 09-2023
Publisher: Elsevier BV
Date: 02-2008
DOI: 10.1016/J.BMCL.2007.12.072
Abstract: CCR2 is the major family of chemokine receptors which involve in the pathophysiology of the acute or chronic inflammatory conditions such as rheumatoid arthritis, atherosclerosis, asthma, obesity, and type-2 diabetes. Herein, we report the results of HQSAR model, developed for CCR2 antagonistic activity of indolopiperidine derivatives. The best HQSAR model with r(2)=0.916, q(2)=0.562 with atom count=4-7 was used to predict the activity of the test set molecules. The predicted values are in good agreement with experimental results and show the potential of the model for untested compounds. Analysis of molecular fragments throws light on essential structural and topological features of indolopiperidine derivatives for antagonist activity. The analysis shows that the presence of tertiary hydrogen bond acceptor groups is important for CCR2 antagonism. Fragments containing benzene ring substituted with one or more chlorine atoms show the positive effect of electron withdrawing group for favorable activity.
Publisher: American Association for Cancer Research (AACR)
Date: 27-07-2023
DOI: 10.1158/2643-3230.23792303.V1
Abstract: JAK2-PK
Publisher: American Society for Pharmacology & Experimental Therapeutics (ASPET)
Date: 17-06-2020
Publisher: American Physiological Society
Date: 04-2019
DOI: 10.1152/PHYSREV.00058.2017
Abstract: UDP-glycosyltransferases (UGTs) catalyze the covalent addition of sugars to a broad range of lipophilic molecules. This biotransformation plays a critical role in elimination of a broad range of exogenous chemicals and by-products of endogenous metabolism, and also controls the levels and distribution of many endogenous signaling molecules. In mammals, the superfamily comprises four families: UGT1, UGT2, UGT3, and UGT8. UGT1 and UGT2 enzymes have important roles in pharmacology and toxicology including contributing to interin idual differences in drug disposition as well as to cancer risk. These UGTs are highly expressed in organs of detoxification (e.g., liver, kidney, intestine) and can be induced by pathways that sense demand for detoxification and for modulation of endobiotic signaling molecules. The functions of the UGT3 and UGT8 family enzymes have only been characterized relatively recently these enzymes show different UDP-sugar preferences to that of UGT1 and UGT2 enzymes, and to date, their contributions to drug metabolism appear to be relatively minor. This review summarizes and provides critical analysis of the current state of research into all four families of UGT enzymes. Key areas discussed include the roles of UGTs in drug metabolism, cancer risk, and regulation of signaling, as well as the transcriptional and posttranscriptional control of UGT expression and function. The latter part of this review provides an in-depth analysis of the known and predicted functions of UGT3 and UGT8 enzymes, focused on their likely roles in modulation of levels of endogenous signaling pathways.
Publisher: Informa UK Limited
Date: 10-05-2016
DOI: 10.1080/03602532.2016.1178771
Abstract: Cytochrome P450 (CYP) family 1, 2, and 3 enzymes play an essential role in the metabolic clearance and detoxification of a myriad of structurally and chemically erse drugs and non-drug xenobiotics. The in idual CYP enzymes exhibit distinct substrate and inhibitor selectivities, and hence differing patterns of inhibitory drug-drug interactions. In addition, CYP enzymes differ in terms of regulation of expression, genetic polymorphism, and environmental factors that alter activity. The availability of three-dimensional structures from X-ray crystallography have been invaluable for understanding the structural basis of the ligand selectivity of CYP enzymes. Moreover, the X-ray crystal structures demonstrate that CYP proteins exhibit marked flexibility, particularly around the active site, and the principle of ligand-induced conformational changes is now well accepted. Recent studies have demonstrated that molecular dynamics simulations (MDS) provide an additional approach for modeling the structural flexibility of CYP enzymes, both in the presence and absence of bound ligand, and understanding the functional consequences of plasticity. However, most of the MDS studies reported to date have utilized short simulation time scales, and few have validated the computationally-generated data experimentally (e.g. by site-directed mutagenesis and enzyme kinetic approaches). Although modeling approaches require further development and validation, MDS has the potential to provide a deeper understanding of CYP structure-function than is available from experimental techniques such as X-ray crystallography alone.
Publisher: Elsevier BV
Date: 11-2019
DOI: 10.1016/J.BCP.2019.08.018
Abstract: We have demonstrated previously that the kinase inhibitors (KIs) lapatinib, pazopanib, regorafenib and sorafenib are potent inhibitors of UGT1A1 and UGTs 1A7-1A10. The present study characterised the effects of four additional drugs in this class, dabrafenib, ibrutinib, nintedanib and trametinib, on human UGT enzyme activities in vitro. Dabrafenib, ibrutinib, nintedanib and trametinib were potent inhibitors of human liver microsomal UGT1A1 K
Publisher: AIP Publishing
Date: 11-07-2011
DOI: 10.1063/1.3604534
Abstract: The relative binding free energy between two ligands to a specific protein can be obtained using various computational methods. The more accurate and also computationally more demanding techniques are the so-called free energy methods which use conformational s ling from molecular dynamics or Monte Carlo simulations to generate thermodynamic averages. Two such widely applied methods are the thermodynamic integration (TI) and the recently introduced enveloping distribution s ling (EDS) methods. In both cases relative binding free energies are obtained through the alchemical perturbations of one ligand into another in water and inside the binding pocket of the protein. TI requires many separate simulations and the specification of a pathway along which the system is perturbed from one ligand to another. Using the EDS approach, only a single automatically derived reference state enveloping both end states needs to be s led. In addition, the choice of an optimal pathway in TI calculations is not trivial and a poor choice may lead to poor convergence along the pathway. Given this, EDS is expected to be a valuable and computationally efficient alternative to TI. In this study, the performances of these two methods are compared using the binding of ten tetrahydroisoquinoline derivatives to phenylethanolamine N-transferase as an ex le. The ligands involve a erse set of functional groups leading to a wide range of free energy differences. In addition, two different schemes to determine automatically the EDS reference state parameters and two different topology approaches are compared.
Publisher: American Association for Cancer Research (AACR)
Date: 09-2023
Publisher: Springer Science and Business Media LLC
Date: 21-11-2014
DOI: 10.1186/S40203-014-0004-8
Abstract: Molecular dynamics (MD) simulation is an emerging in silico technique with potential applications in erse areas of pharmacology. Over the past three decades MD has evolved as an area of importance for understanding the atomic basis of complex phenomena such as molecular recognition, protein folding, and the transport of ions and small molecules across membranes. The application of MD simulations in isolation and in conjunction with experimental approaches have provided an increased understanding of protein structure-function relationships and demonstrated promise in drug discovery.
Publisher: American Chemical Society (ACS)
Date: 15-11-2011
DOI: 10.1021/CT200196M
Abstract: The Automated force field Topology Builder (ATB, compbio.biosci.uq.edu.au/atb ) is a Web-accessible server that can provide topologies and parameters for a wide range of molecules appropriate for use in molecular simulations, computational drug design, and X-ray refinement. The ATB has three primary functions: (1) to act as a repository for molecules that have been parametrized as part of the GROMOS family of force fields, (2) to act as a repository for pre-equilibrated systems for use as starting configurations in molecular dynamics simulations (solvent mixtures, lipid systems pre-equilibrated to adopt a specific phase, etc.), and (3) to generate force field descriptions of novel molecules compatible with the GROMOS family of force fields in a variety of formats (GROMOS, GROMACS, and CNS). Force field descriptions of novel molecules are derived using a multistep process in which results from quantum mechanical (QM) calculations are combined with a knowledge-based approach to ensure compatibility (as far as possible) with a specific parameter set of the GROMOS force field. The ATB has several unique features: (1) It requires that the user stipulate the protonation and tautomeric states of the molecule. (2) The symmetry of the molecule is analyzed to ensure that equivalent atoms are assigned identical parameters. (3) Charge groups are assigned automatically. (4) Where the assignment of a given parameter is ambiguous, a range of possible alternatives is provided. The ATB also provides several validation tools to assist the user to assess the degree to which the topology generated may be appropriate for a given task. In addition to detailing the steps involved in generating a force field topology compatible with a specific GROMOS parameter set (GROMOS 53A6), the challenges involved in the automatic generation of force field parameters for atomic simulations in general are discussed.
Publisher: American Association for Cancer Research (AACR)
Date: 27-07-2023
DOI: 10.1158/2643-3230.23792318.V1
Abstract: Figure showing X-ray crystal structure of pseudokinase domain inhibitor
Publisher: American Society for Pharmacology & Experimental Therapeutics (ASPET)
Date: 15-12-2015
Abstract: Although there is evidence for an important role of UGT2B10 in the N-glucuronidation of drugs and other xenobiotics, the inhibitor selectivity of this enzyme is poorly understood. This study sought primarily to characterize the inhibition selectivity of UGT2B10 by UDP-glucuronosyltransferase (UGT) enzyme-selective inhibitors used for reaction phenotyping, and 34 antidepressant and antipsychotic drugs that contain an amine functional group. Initial studies demonstrated that cotinine is a highly selective substrate of human liver microsomal UGT2B10. The kinetics of cotinine N-glucuronidation by recombinant UGT and human liver microsomes (± bovine serum albumin) were consistent with the involvement of a single enzyme. Of the UGT enzyme-selective inhibitors employed for reaction phenotyping, only the UGT2B4/7 inhibitor fluconazole reduced recombinant UGT2B10 activity to an appreciable extent. The majority of antidepressant and antipsychotic drugs screened for effects on UGT2B10 inhibited enzyme activity with IC50 values <100 µM. The most potent inhibition was observed with the tricyclic antidepressants amitriptyline and doxepin and the tetracyclic antidepressant mianserin, and the structurally related compounds desloratadine and loratadine. Molecular modeling using a ligand-based approach indicated that hydrophobic and charge interactions are involved in inhibitor binding, whereas spatial features influence the potency of UGT2B10 inhibition. Respective mean Ki,u (± S.D.) values for amitriptyline, doxepin, and mianserin inhibition of human liver microsomal UGT2B10 were 0.61 ± 0.05, 0.95 ± 0.18, and 0.43 ± 0.01 µM. In vitro-in vivo extrapolation indicates that these drugs may perpetrate inhibitory drug-drug interactions when coadministered with compounds that are cleared predominantly by UGT2B10.
Publisher: SAGE Publications
Date: 19-07-2023
Publisher: Hong Kong Academy of Medicine Press
Date: 28-03-2023
DOI: 10.12809/EAAP2237
Publisher: American Chemical Society (ACS)
Date: 16-02-2012
DOI: 10.1021/ML300015U
Publisher: American Chemical Society (ACS)
Date: 03-09-2008
DOI: 10.1021/CI800157J
Abstract: Chemokine receptors have evolved as attractive targets for disease conditions which arise due to immunomodulation involving host-defense mechanisms. CCR2, a chemokine receptor, is targeted for diseases like arthritis, multiple sclerosis, vascular disease, obesity, and type 2 diabetes. This study provides a new strategy of a ligand based technique which exploits fingerprint led fragment features in conjunction with structure-guided design for identifying new scaffolds for CCR2. A fragment based mining (FBM) technique was employed on a chemical database to identify novel scaffold hops. The hits were subjected to 3-point pharmacophore fingerprint procedures with Tanimoto similarity metric to compare pharmacophoric fingerprints. The final 66 hits generated by these exercises were predicted by the validated HQSAR model, and the top predicted were suggested as probable scaffolds for CCR2 antagonism. The identified scaffolds were validated through molecular docking studies. The ligands were docked by providing receptor flexibility in the extra cellular domain (1 and 3), N terminal domain, and in the transmembrane (TM1 & TM7) helix region with IFD approach. Some of the scaffolds showed H-bonding potential which was not explored by the data set molecules. All identified scaffolds highlighted a key hydrogen bonding interaction with Thr292 as supported by mutational studies. The observed pi stacking interaction with Tyr188 in data set molecules was also produced by the new scaffolds. Taking the advantage of receptor flexibility the scaffolds explored the hydrophobic binding cleft between helix 1 and 7 occupied by residues Leu44, Leu45, Leu48 and Ile300, Ile303, Ile304, respectively. Two of the identified molecules have promising outcomes and can be considered as novel scaffolds for CCR2 binding.
Publisher: American Association for Cancer Research (AACR)
Date: 27-07-2023
DOI: 10.1158/2643-3230.C.6762722.V1
Abstract: Abstract Selective inhibitors of Janus kinase (JAK) 2 have been in demand since the discovery of the JAK2 V617F mutation present in patients with myeloproliferative neoplasms (MPN) however, the structural basis of V617F oncogenicity has only recently been elucidated. New structural studies reveal a role for other JAK2 domains, beyond the kinase domain, that contribute to pathogenic signaling. Here we evaluate the structure-based approaches that led to recently-approved type I JAK2 inhibitors (fedratinib and pacritinib), as well as type II (BBT594 and CHZ868) and pseudokinase inhibitors under development (JNJ7706621). With full-length JAK homodimeric structures now available, superior selective and mutation-specific JAK2 inhibitors are foreseeable. Significance: The JAK inhibitors currently used for the treatment of MPNs are effective for symptom management but not for disease eradication, primarily because they are not strongly selective for the mutant clone. The rise of computational and structure-based drug discovery approaches together with the knowledge of full-length JAK dimer complexes provides a unique opportunity to develop better targeted therapies for a range of conditions driven by pathologic JAK2 signaling. /
Publisher: Bentham Science Publishers Ltd.
Date: 2011
DOI: 10.2174/187152011794941181
Abstract: Phosphatases are well known drug targets for diseases such as diabetes, obesity and other autoimmune diseases. Their role in cancer is due to unusual expression patterns in different types of cancer. However, there is strong evidence for selective targeting of phosphatases in cancer therapy. Several experimental and in silico techniques have been attempted for design of phosphatase inhibitors, with focus on diseases such as diabetes, inflammation and obesity. Their utility for cancer therapy is limited and needs to be explored vastly. Quantitative Structure Activity relationship (QSAR) is well established in silico ligand based drug design technique, used by medicinal chemists for prediction of ligand binding affinity and lead design. These techniques have shown promise for subsequent optimization of already existing lead compounds, with an aim of increased potency and pharmacological properties for a particular drug target. Furthermore, their utility in virtual screening and scaffold hopping is highlighted in recent years. This review focuses on the recent molecular field analysis (MFA) and QSAR techniques, directed for design and development of phosphatase inhibitors and their potential use in cancer therapy. In addition, this review also addresses issues concerning the binding orientation and binding conformation of ligands for alignment sensitive QSAR approaches.
Publisher: Springer Science and Business Media LLC
Date: 09-01-2019
DOI: 10.1208/S12248-018-0262-1
Abstract: The multi-kinase inhibitor sorafenib (SOR) is clinically important in the treatment of hepatocellular and renal cancers and undergoes CYP3A4-dependent oxidation in liver to the pharmacologically active N-oxide metabolite (SNO). There have been reports that kinase inhibitors such as SOR may precipitate pharmacokinetic interactions with coadministered drugs that compete for CYP3A4-mediated biotransformation, but these occur non-uniformly in patients. Clinical evidence also indicates that SNO accumulates in serum of some patients during prolonged SOR therapy. In this study undertaken in hepatic microsomes from in idual donors, we assessed the possibility that SNO might contribute to pharmacokinetic interactions mediated by SOR. Enzyme kinetics of CYP3A4-mediated midazolam 1'-hydroxylation in in idual human hepatic microsomes were analyzed by non-linear regression and appropriate replots. Thus, SNO and SOR were linear-mixed inhibitors of microsomal CYP3A4 activity (K
Publisher: American Association for Cancer Research (AACR)
Date: 27-07-2023
DOI: 10.1158/2643-3230.BCD-22-0189
Abstract: The JAK inhibitors currently used for the treatment of MPNs are effective for symptom management but not for disease eradication, primarily because they are not strongly selective for the mutant clone. The rise of computational and structure-based drug discovery approaches together with the knowledge of full-length JAK dimer complexes provides a unique opportunity to develop better targeted therapies for a range of conditions driven by pathologic JAK2 signaling.
Publisher: American Association for Cancer Research (AACR)
Date: 27-07-2023
DOI: 10.1158/2643-3230.23792312
Abstract: JAK2-monomer-500ns.pdb. (Structure of human JAK2 monomer at 500 ns simulation).
Publisher: Elsevier BV
Date: 02-2008
DOI: 10.1016/J.EJMECH.2007.03.020
Abstract: Influenza virus is a major global threat that impacts the world in one form or another as flu infections. Neuraminidase, one of the targets for these viruses, has recently been exploited in the treatment of these infections. Quantitative structure activity relationship studies were performed on thiourea analogues using spatial, topological, electronic, thermodynamic and E-state indices. Genetic algorithm based genetic function approximation method of variable selection was used to generate the model. Highly statistically significant model was obtained when number of descriptors in the equation was set to 5. The atom type log P and shadow indices descriptors showed enormous contributions to neuraminidase inhibition. The validation of the model was done by cross validation, randomization and external test set prediction. The model gives insight on structural requirements for designing more potent analogues against influenza virus neuraminidase.
Publisher: American Association for Cancer Research (AACR)
Date: 27-07-2023
DOI: 10.1158/2643-3230.23792315
Abstract: JAK2-monomer-0ns.pdb. (Model of human JAK2 monomer used for molecular dynamics simulation).
Publisher: American Association for Cancer Research (AACR)
Date: 27-07-2023
DOI: 10.1158/2643-3230.23792315.V1
Abstract: JAK2-monomer-0ns.pdb. (Model of human JAK2 monomer used for molecular dynamics simulation).
Publisher: American Association for Cancer Research (AACR)
Date: 27-07-2023
DOI: 10.1158/2643-3230.23792318
Abstract: Figure showing X-ray crystal structure of pseudokinase domain inhibitor
Publisher: Springer Singapore
Date: 2021
Publisher: American Society for Pharmacology & Experimental Therapeutics (ASPET)
Date: 06-10-2015
Abstract: Drugs and other chemicals frequently bind nonspecifically to the constituents of an in vitro incubation mixture, particularly the enzyme source [e.g., human liver microsomes (HLM)]. Correction for nonspecific binding (NSB) is essential for the accurate calculation of the kinetic parameters Km, Clint, and Ki. Many tyrosine kinase inhibitors (TKIs) are lipophilic organic bases that are nonionized at physiologic pH. Attempts to measure the NSB of several TKIs to HLM by equilibrium dialysis proved unsuccessful, presumably due to the limited aqueous solubility of these compounds. Thus, the addition of detergents to equilibrium dialysis s les was investigated as an approach to measure the NSB of TKIs. The binding of six validation set nonionized lipophilic bases (felodipine, isradipine, loratidine, midazolam, nifedipine, and pazopanib) to HLM (0.25 mg/ml) was shown to be unaffected by the addition of CHAPS (6 mM) to the dialysis medium. This approach was subsequently applied to measurement of the binding of axitinib, dabrafenib, erlotinib, gefitinib, ibrutinib, lapatinib, nilotinib, nintedanib, regorafenib, sorafenib, and trametinib to HLM (0.25 mg/ml). As with the validation set drugs, attainment of equilibrium was demonstrated in HLM-HLM and buffer-buffer control dialysis experiments. Values of the fraction unbound to HLM ranged from 0.14 (regorafenib and sorafenib) to 0.93 (nintedanib), and were generally consistent with the known physicochemical determinants of drug NSB. The extensive NSB of many TKIs to HLM underscores the importance of correction for TKI binding to HLM and, presumably, other enzyme sources present in in vitro incubation mixtures.
Publisher: American Association for Cancer Research (AACR)
Date: 09-2023
Publisher: Elsevier BV
Date: 07-2007
DOI: 10.1016/J.JMGM.2006.10.002
Abstract: PTP1B plays an important role as a negative regulator in insulin and leptin signaling pathways. Potent and orally active PTP1B inhibitors can act as potential agents for the treatment of Type 2 diabetes and obesity. CoMFA (Comparative Molecular Field Analysis) and de novo ligand design using LeapFrog (LF) studies were performed on pyridazine analogs, reported to be selective and non-competitive inhibitors of PTP1B. A robust model was developed which produced statistically significant results with cross-validated and conventional correlation coefficients of 0.619 and 0.990, respectively. Further, the robustness of the model was verified by bootstrapping analysis. LeapFrog (LF) program is a de novo drug discovery tool, which uses CoMFA maps to generate hypothetical cavity and ligands. As the crystal structure of PTP1B-pyridazine complex is not yet known, the contours of CoMFA model was used to serve as a pharmacophoric model to generate hypothetical cavity for LeapFrog calculations. Ligands were optimized using this concept.
Publisher: American Society for Pharmacology & Experimental Therapeutics (ASPET)
Date: 17-12-2015
Abstract: The human UDP glycosyltransferase (UGT) superfamily comprises four families of enzymes that catalyze the addition of sugar residues to small lipophilic chemicals. The UGT1 and UGT2 enzymes use UDP-glucuronic acid, and UGT3 enzymes use UDP-N-acetylglucosamine, UDP-glucose, and UDP-xylose to conjugate xenobiotics, including drugs and endobiotics such as metabolic byproducts, hormones, and signaling molecules. This metabolism renders the substrate more polar and more readily excreted from the body and/or functionally inactive. The fourth UGT family, called UGT8, contains only one member that, unlike other UGTs, is considered biosynthetic. UGT8 uses UDP galactose to galactosidate ceramide, a key step in the synthesis of brain sphingolipids. To date other substrates for this UGT have not been identified and there has been no suggestion that UGT8 is involved in metabolism of endo- or xenobiotics. We re-examined the functions of UGT8 and discovered that it efficiently galactosidates bile acids and drug-like bile acid analogs. UGT8 conjugates bile acids ∼60-fold more efficiently than ceramide based on in vitro assays with substrate preference deoxycholic acid > chenodeoxycholic acid > cholic acid > hyodeoxycholic acid > ursodeoxycholic acid. Activities of human and mouse UGT8 are qualitatively similar. UGT8 is expressed at significant levels in kidney and gastrointestinal tract (intestine, colon) where conjugation of bile acids is likely to be metabolically significant. We also investigate the structural determinants of UDP-galactose selectivity. Our novel findings suggest a new role for UGT8 as a modulator of bile acid homeostasis and signaling.
Publisher: American Association for Cancer Research (AACR)
Date: 27-07-2023
DOI: 10.1158/2643-3230.23792309.V1
Abstract: Supplementary Information: Figure S1 X-ray crystal structure of JNJ-77006621(ball and stick, C-atoms in green) bound to JAK2-PK domain (cartoon, yellow). Key residues are displayed in sticks [C-atoms in green near the optimisation domain (Peuleo et al. 2017, Liosi et al 2020) and C-atoms in yellow at the dimerization domain]. Supplementary Methods.
Publisher: Elsevier BV
Date: 10-2023
Publisher: Springer Science and Business Media LLC
Date: 09-06-2023
DOI: 10.1038/S41467-023-38467-9
Abstract: Dimethylarginine dimethylaminohydrolase 1 (DDAH1) protects against cardiovascular disease by metabolising the risk factor asymmetric dimethylarginine (ADMA). However, the question whether the second DDAH isoform, DDAH2, directly metabolises ADMA has remained unanswered. Consequently, it is still unclear if DDAH2 may be a potential target for ADMA-lowering therapies or if drug development efforts should focus on DDAH2’s known physiological functions in mitochondrial fission, angiogenesis, vascular remodelling, insulin secretion, and immune responses. Here, an international consortium of research groups set out to address this question using in silico, in vitro, cell culture, and murine models. The findings uniformly demonstrate that DDAH2 is incapable of metabolising ADMA, thus resolving a 20-year controversy and providing a starting point for the investigation of alternative, ADMA-independent functions of DDAH2.
Publisher: Elsevier BV
Date: 10-2022
DOI: 10.1016/J.BMC.2022.116970
Abstract: Nitric oxide (NO) is a signalling molecule that controls a multitude of regulatory functions including neurotransmission, vascular tone, immune response, and angiogenesis. Regulating NO concentrations in cells using small molecules is an active area of research in the treatment of several pathologies such as cardiovascular disease, cancer, and inflammatory conditions. Small molecule-inhibition of critical NO regulatory enzymes, NO synthase (NOS), arginase, and dimethylarginine dimethyaminohydrolase-1 (DDAH1), has shown therapeutic benefits as well as limitations and is a focus of current research.In recent years, DDAH1 has been explored as a potential target to indirectly regulate NO in diseases characterized by excessive NO production. This review discusses the biological and pathophysiological role of the NO pathway, the existing inhibitors of NOS, arginase and DDAH1, and the conventional and structure-guided structure-activity relationship studies involved in their discovery. The key structural elements of amino acid-derived inhibitors responsible for selective inhibition of each enzyme, and the chemical features responsible for dual enzyme inhibition are also discussed. Finally, a synthetic scheme for developing both selective and dual inhibitors using common starting materials is provided, offering unique insights in the quest for the rational design of novel NO pathway inhibitors.
Publisher: SAGE Publications
Date: 10-05-2022
Publisher: Springer Science and Business Media LLC
Date: 13-03-2020
DOI: 10.1038/S41380-020-0709-5
Abstract: Clozapine is the gold-standard agent for treatment resistant schizophrenia but its mechanism of action remains unclear. There is emerging evidence of the potential role of the GABA
Publisher: American Association for Cancer Research (AACR)
Date: 09-2023
Publisher: Elsevier BV
Date: 04-2021
Publisher: Elsevier BV
Date: 12-2019
DOI: 10.1016/J.PHARMTHERA.2019.107414
Abstract: The UDP glycosyltransferase (UGT) superfamily of enzymes is responsible for the metabolism and clearance of thousands of lipophilic chemicals including drugs, toxins and endogenous signaling molecules. They provide a protective interface between the organism and its chemical-rich environment, as well as controlling critical signaling pathways to maintain healthy tissue function. UGTs are associated with drug responses and interactions, as well as a wide range of diseases including cancer. The human genome contains 22 UGT genes however as befitting their exceptionally erse substrate ranges and biological activities, the output of these UGT genes is functionally ersified by multiple processes including alternative splicing, post-translational modification, homo- and hetero-oligomerization, and interactions with other proteins. All UGT genes are subject to extensive alternative splicing generating variant/truncated UGT proteins with altered functions including the capacity to dominantly modulate/inhibit cognate full-length forms. Heterotypic oligomerization of different UGTs can alter kinetic properties relative to monotypic complexes, and potentially produce novel substrate specificities. Moreover, the recently profiled interactions of UGTs with non-UGT proteins may facilitate coordination between different metabolic processes, as well as providing opportunities for UGTs to engage in novel 'moonlighting' functions. Herein we provide a detailed and comprehensive review of all known modes of UGT functional ersification and propose a UGTome model to describe the resulting expansion of metabolic capacity and its potential to modulate drug/xenobiotic responses and cell behaviours in normal and disease contexts.
Publisher: American Association for Cancer Research (AACR)
Date: 09-2023
Publisher: American Society for Pharmacology & Experimental Therapeutics (ASPET)
Date: 02-10-2020
Publisher: American Association for Cancer Research (AACR)
Date: 27-07-2023
DOI: 10.1158/2643-3230.23792303
Abstract: JAK2-PK
Publisher: American Association for Cancer Research (AACR)
Date: 09-2023
Publisher: American Association for Cancer Research (AACR)
Date: 27-07-2023
DOI: 10.1158/2643-3230.23792309
Abstract: Supplementary Information: Figure S1 X-ray crystal structure of JNJ-77006621(ball and stick, C-atoms in green) bound to JAK2-PK domain (cartoon, yellow). Key residues are displayed in sticks [C-atoms in green near the optimisation domain (Peuleo et al. 2017, Liosi et al 2020) and C-atoms in yellow at the dimerization domain]. Supplementary Methods.
Publisher: American Association for Cancer Research (AACR)
Date: 27-07-2023
DOI: 10.1158/2643-3230.23792312.V1
Abstract: JAK2-monomer-500ns.pdb. (Structure of human JAK2 monomer at 500 ns simulation).
Publisher: American Association for Cancer Research (AACR)
Date: 09-2023
DOI: 10.1158/2643-3230.C.6762722
Abstract: Abstract Selective inhibitors of Janus kinase (JAK) 2 have been in demand since the discovery of the JAK2 V617F mutation present in patients with myeloproliferative neoplasms (MPN) however, the structural basis of V617F oncogenicity has only recently been elucidated. New structural studies reveal a role for other JAK2 domains, beyond the kinase domain, that contribute to pathogenic signaling. Here we evaluate the structure-based approaches that led to recently-approved type I JAK2 inhibitors (fedratinib and pacritinib), as well as type II (BBT594 and CHZ868) and pseudokinase inhibitors under development (JNJ7706621). With full-length JAK homodimeric structures now available, superior selective and mutation-specific JAK2 inhibitors are foreseeable. Significance: The JAK inhibitors currently used for the treatment of MPNs are effective for symptom management but not for disease eradication, primarily because they are not strongly selective for the mutant clone. The rise of computational and structure-based drug discovery approaches together with the knowledge of full-length JAK dimer complexes provides a unique opportunity to develop better targeted therapies for a range of conditions driven by pathologic JAK2 signaling. /
Publisher: American Association for Cancer Research (AACR)
Date: 09-2023
Publisher: American Society for Pharmacology & Experimental Therapeutics (ASPET)
Date: 19-08-2016
Abstract: Correction for the nonspecific binding (NSB) of drugs to liver microsomes is essential for the accurate measurement of the kinetic parameters K
Publisher: American Association for Cancer Research (AACR)
Date: 09-2023
Publisher: American Association for Cancer Research (AACR)
Date: 09-2023
Publisher: Springer Science and Business Media LLC
Date: 21-10-2019
DOI: 10.1208/S12248-019-0374-2
Abstract: The multikinase inhibitor sorafenib (SOR) is used to treat patients with hepatocellular and renal carcinomas. SOR undergoes CYP-mediated biotransformation to a pharmacologically active N-oxide metabolite (SNO) that has been shown to accumulate to varying extents in in iduals. Kinase inhibitors like SOR are frequently coadministered with a range of other drugs to improve the efficacy of anticancer drug therapy and to treat comorbidities. Recent evidence has suggested that SNO is more effective than SOR as an inhibitor of CYP3A4-mediated midazolam 1'-hydroxylation. CYP2D6 is also reportedly inhibited by SOR. The present study assessed the possibility that SNO might contribute to CYP2D6 inhibition. The inhibition kinetics of CYP2D6-mediated dextromethorphan O-demethylation were analyzed in human hepatic microsomes, with SNO found to be ~ 19-fold more active than SOR (K
Publisher: American Association for Cancer Research (AACR)
Date: 09-2023
Start Date: 06-2020
End Date: 09-2023
Amount: $550,000.00
Funder: Australian Research Council
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